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 Table of Contents  
DR WATSON’S CLINICAL MYSTERY
Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 140-142

The tale of a diagnostic conundrum


1 Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Date of Submission01-Mar-2021
Date of Decision21-Mar-2021
Date of Acceptance30-Apr-2021
Date of Web Publication31-May-2021

Correspondence Address:
Dr. Sriram Krishnamurthy
Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantari Nagar, Puducherry - 605 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ipcares.ipcares_64_21

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How to cite this article:
Deepthi B, Krishnamurthy S, Shivaprasad P M, Minnaladevi M, Ganesh RN. The tale of a diagnostic conundrum. Indian Pediatr Case Rep 2021;1:140-2

How to cite this URL:
Deepthi B, Krishnamurthy S, Shivaprasad P M, Minnaladevi M, Ganesh RN. The tale of a diagnostic conundrum. Indian Pediatr Case Rep [serial online] 2021 [cited 2021 Sep 21];1:140-2. Available from: http://www.ipcares.org/text.asp?2021/1/2/140/317363


  Recreation of the scene of the crime… Top


A 12-year-old boy presented to the emergency with a history of low-grade, intermittent fever for 4 days. He had painful swelling of both knees for the same duration that was causing painful restriction of movements. No other joints were involved. He also had breathlessness for 2 days that had initially been on exertion but was now occurring at rest and worsened on lying supine. Swelling had appeared around his eyes and over his feet for 2 days. There was decreased frequency of urination, but no discoloration had been noted. There was no history of any chest pain, palpitations, rashes, appearance of small nodules, or abnormal movements. There was no history of skin lesions or sore throat in the recent past. He gave a significant history of a previous episode of migratory, asymmetrical painful joint swellings involving both knees, elbows, left wrist, and right ankle 2 years earlier, for which he was treated and the medication was still continuing.

On examination, he was febrile (39.4°C), had tachycardia (104 beats/min), and increased respiratory rate (26/min). All pulses were well felt, with no particular character. The jugular venous pressure was elevated (6 cm above the sternal angle). The blood pressure was 140/90 mmHg (>95th centile). His weight was 36 kg (0 to −1 Z score), height was 150 cm (0 to −1 Z score), and body mass index was 16 (0 to −1 Z score). General physical examination revealed pallor, periorbital puffiness, and bilateral pedal edema. Both knees showed features suggestive of arthritis. No skin lesions, rashes, erythema marginatum, or subcutaneous nodules were noted. Examination revealed a hyperdynamic apex with high-pitched Grade 2 pansystolic murmur best heard in the mitral area and bilateral basal crepitations.

Dr Watson: Could this be congestive heart failure (CHF), secondary to rheumatic heart disease? (RHD) Let me elicit some more pertinent clinical details.

It was discovered that the child had been diagnosed with acute rheumatic fever (ARF) and treated with oral steroids and aspirin for 12 weeks in the previous episode. There had been a rapid therapeutic response, with the joint pain and swelling abating within 48–72 h, any no residual deformities. On follow-up, the child had developed moderate mitral regurgitation, deemed secondary to RHD. He had been advised prophylactic therapy with oral penicillin. However, compliance had been poor in the past 3 months.

Dr Watson: Hmm, but what could be the cause of oliguria in this case?

In a setting of CHF, oliguria could be due to left ventricular dysfunction leading to peripheral circulatory failure. However, the absence of hypotension made this unlikely. Instead, he had hypertension, periorbital puffiness, and pedal edema, all features of fluid overload. These suggested that an intrinsic acute kidney injury (AKI) superimposed on an underlying cardiac abnormality be considered.

Dr Watson: If this is AKI, what could be the cause?

AKI in ARF could be due to infective endocarditis (IE) associated with glomerulonephritis (GN). Let me order an Echocardiogram and other supportive investigations.

The hemoglobin level was 6.6 g/dL, total leukocyte count of 19.4 × 109/L (77% polymorphs, 10% lymphocytes, and 11% monocytes), and platelet count of 5.5 × 109/L. Peripheral smear showed microcytic hypochromic anemia with no evidence of hemolysis. Erythrocyte sedimentation rate (ESR) was elevated (120 mm/h). The renal function tests were grossly deranged (blood urea 166 mg/dL and serum creatinine 3.6 mg/dL). When compared with reports available from 3 months ago, the rise in serum creatinine was thrice the baseline (0.7 mg/dL), which confirmed AKI stage 3.[1] Serum Na+ was 136 mEq/L and K+ was 6 mEq/L. C-reactive protein was negative. Antistreptolysin 0 (ASLO) was raised (430 IU/mL). Serial blood cultures were sterile and throat swab culture negative for Streptococcus pyogenes. A renal ultrasonogram revealed normal kidney sizes (right 8.5 cm and left 8.6 cm) with mildly increased echogenicity. Chest X-ray showed cardiomegaly, electrocardiogram was normal, and echocardiogram showed severe mitral regurgitation with anterior mitral leaflet thickening and no restriction of leaflet movement, or vegetations.

Dr Watson: Let me synthesize the clinical findings and investigation reports

Clinical diagnosis of recurrence of ARF in an established RHD is made in the presence of either 2 major or 1 major and 2 minor or 3 minor criteria with evidence of preceding Group A streptococci (GAS) infection. In this case, two major (arthritis and carditis) and two minor criteria (fever >38.5°F and ESR >30 mm) are satisfied with increased ASLO titers.

Dr Watson: Do I need to order any other investigations?

Urinalysis is an indispensable investigation in AKI for delineating etiology. The child's urinalysis revealed microscopic hematuria (100 dysmorphic red blood cells (RBCs)/ High power field (HPF) with RBC casts) and proteinuria 1+. The urine protein to urine creatine ratio was 0.4. These findings suggested acute GN (AGN) as the cause for AKI. Severe AKI in a setting of AGN means that rapidly progressive GN (RPGN) could be a likely diagnosis, the histopathological hallmark of which is crescentic GN.

Dr Watson: Could this be IE-associated GN?

The child had fever but no other clinical correlates of IE including splenomegaly, Janeway lesions, Roth spots, splinter hemorrhages, or Osler's nodes. Serial blood cultures were sterile, and the echocardiogram revealed no vegetations. These ruled out IE-associated AGN.

Dr Watson: This needs further workup. I believe a renal biopsy is also in order.

Renal biopsy reveals crescentic GN. Out of 25 glomeruli, 50% had crescents that were predominantly cellular [Figure 1], in addition to 1 fibro cellular, 1 fibrous crescent, and 1 globally sclerosed glomeruli with immune complex deposition (IgG-2+ and C3-3+). The serum C3 levels were 204 mg/dL (normal 90–180 mg/dL); antineutrophilic cytoplasmic antibodies were negative. The final diagnosis is crescentic GN (immune complex mediated).
Figure 1: Figure section shows glomerulus with circumferential cellular crescent, with mesangial matrix expansion, hematoxylin and eosin stain, ×200

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Dr Watson: Early treatment of crescentic GN is crucial to prevent progression to end-stage renal disease. Let's start prompt immunosuppression.

The child is given intravenous (IV) methylprednisolone pulses for 5 days followed by IV, as per standard treatment protocol. The urine output and symptoms improved with diuretics and immunosuppressive therapy. Dialysis is not required.

Dr Watson: Let me check the diagnostic algorithm for RPGN to ascertain etiology.

Dr Watson reviews [Figure 2]. The lack of respiratory symptoms, sinusitis, negative ANCA, and presence of immune deposits rules out Wegener's granulomatosis. Antiglomerular basement membrane disease (GBM) is excluded by the absence of anti-GBM antibodies and rapid improvement in symptoms without need for plasmapheresis. Among the immune-mediated GN, immunoglobulin (IgA) nephropathy is ruled out in the absence of mesangial IgA deposits. Lupus nephritis is eliminated by the absence of symptoms and signs of systemic lupus erythematosus and the absence of full house immune positivity. Poststreptococcal GN (PSGN) could be considered, especially since the biopsy showed crescentic GN with IgG and C3 deposits in the glomerular capillary walls. However, PSGN is characterized by hypocomplementemia and in this case, the C3 levels were normal. Hence, PSGN becomes less likely.
Figure 2: Algorithm for differential diagnosis of rapidly progressive glomerulonephritis

Click here to view


Dr Watson: Could this be membranoproliferative glomerulonephritis (MPGN)?

Since the aforementioned causes of crescentic GN were excluded, MPGN is definitely likely in the presence of globally sclerosed glomeruli on the light microscopy and immune complex deposits on immune fluorescence, since normal C3 levels are described in 30% cases of MPGN.[1] Features such as basement membrane splitting and lobular accentuation of the glomeruli may not always be appreciated in early stages of MPGN.

Dr Watson: Let me complete my case diary by adding the details of the follow-up.

After the initial IV pulse of steroids, the child was put on tapering doses of oral prednisolone (2 mg/kg/day daily to 0.3 mg/kg/day on alternate days). He has received 6 pulses of monthly IV Cyclophosphamide so far. The estimated glomerular filtration rate (eGFR) at the end of 6 months is 82 ml/min/1.73 m2, implying residual renal injury and chronic kidney disease stage 2. This clinical course further favors MPGN.

If Holmes was here, I would have been the one saying 'Elementary, my dear Sherlock!'.


  Discussion Top


We have described a case of RHD with ARF in a child, complicated by RPGN. The most common cause of GN in RHD is IE, which is seen in 18%–25% cases of IE.[2] However, it is mostly asymptomatic. When symptoms do occur in IE, it is usually due to acute nephritic syndrome, rarely as RPGN.[3],[4] ARF and GN have been reported in RHD in the absence of IE,[5] although in adults. It was postulated that the causative organism would be a common rheumatogenic and nephritogenic Group A streptococcal strain, possibly strain M1, that is known to trigger both ARF and PSGN, since both are pathogenetically distinct entities. While ARF is speculated to be due to molecular mimicry, PSGN is proposed to be due to the binding of nephritis-associated plasmin receptor and streptococcal pyrogenic exotoxin B to glomeruli, inducing immune complex deposits.[4]

MPGN has been reported in an adult with ARF.[6] To reiterate, MPGN is the likely cause of crescentic GN in our patient, since 30%–40% of MPGN may have normal complement levels at presentation, and distinction of early MPGN from infection-related GN is difficult on light microscopy. The concurrent occurrence of immune complex-mediated MPGN and ARF is very rare. We were unable to isolate GAS strain M1 due to logistic constraints. Another limitation was absence of electron microscopy which could have established the diagnosis of MPGN by demonstration of subendothelial and intramembranous immunoglobulin G and C3 deposits.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline on glomerulonephritis. Kidney Int Suppl 2012;2:139-274.  Back to cited text no. 1
    
2.
Krishnamurthy S, Chandrasekaran V, Mahadevan S, Priyamvada PS, Rajesh NG. Severe acute kidney injury in children owing to infective endocarditis-associated immune complex glomerulonephritis: A report of two cases. Paediatr Int Child Health 2017;37:144-7.  Back to cited text no. 2
    
3.
Sadikoglu B, Bilge I, Kilicaslan I, Gokce MG, Emre S, Ertugrul T. Crescentic glomerulonephritis in a child with infective endocarditis. Pediatr Nephrol 2006;21:867-9.  Back to cited text no. 3
    
4.
Mantan M, Sethi GR, Batra VV. Post-infectious glomerulonephritis following infective endocarditis: Amenable to immunosuppression. Indian J Nephrol 2013;23:368-70.  Back to cited text no. 4
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5.
Nakauyaca AV, Ralph AP, Majoni WS, Kangaharan N. Case report: Concurrent rheumatic fever and acute post-streptococcal glomerulonephritis in a high-burden setting. Am J Trop Med Hyg 2019;101:1054-7.  Back to cited text no. 5
    
6.
Mendoza N, Mandalenakis N, Kanter A, Pirani CL, Pollak VE. Chronic membranoproliferative glomerulonephritis. A patient with recurrent episodes simulating rheumatic fever and acute nephritis. Am J Med 1975;59:251-61.  Back to cited text no. 6
    


    Figures

  [Figure 1], [Figure 2]



 

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